Cancer is the second leading cause of human death next to coronary disease. Worldwide, millions of people die from cancer every year. In the United States alone, cancer causes the death of well over a half-million people annually, with some 1.4 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise.
Worldwide, several cancers stand out as the leading killers. In particular, carcinomas of the breast, lung, prostate, colon, pancreas, and ovary represent the primary causes of cancer death. These and virtually all other carcinomas share a common lethal feature. With very few exceptions, metastatic disease from a carcinoma is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered and many cancer patients experience a recurrence.
Breast cancer affects over one million women worldwide every year (see, e.g., Jemal A et al., 2002. CA Cancer J. Clin. 2002 January-February; 52(1):23-47; Jensen O M, et al., Eur. J. Cancer. 1990; 26(11-12):1167-256; and National Cancer Institute of Canada: Canadian Cancer Statistics 1996. Toronto, Canada. 1996; 21-23). Breast cancer is also one of the leading causes of death among women, with the cumulative lifetime risk of a woman developing breast cancer estimated to be 1 in 9. Understanding the origins and subtypes of these malignancies as well as models for the identification of new diagnostic and therapeutic modalities is of significant interest to health care professionals. Most women that die from breast cancer succumb not to the original primary disease, which is usually amenable to various therapies, but rather from metastatic spread of the breast cancer to distant sites. This fact underscores the need to develop both additional diagnostic methods as well as novel anticancer agents or more aggressive forms of therapy directed specifically against breast tumor subtypes.
Advances in the understanding of the biology of this disease, however, have led to improved patient survival with incorporation of new anti-hormonal agents in the treatment of hormone receptor positive disease and the addition of HER2 directed therapies for the 25% of women with HER2 amplification (see, e.g., Fossati R, et al., J. Clin. Oncol. 1998 October; 16(10):3439-60 and Slamon D J, et al., N Engl J. Med. 2001 Mar. 15; 344(11):783-92).
There remains however, a subset of women for whom these approaches are not an effective option and chemothorapy offers only limited benefits. This group has been described as “triple negative” (i.e. estrogen receptor negative (SEQ ID NO: 7), progesterone receptor negative (SEQ ID NO: 8), and HER2 negative (SEQ ID NO: 9)) and represents a distinct clinical and molecular subgroup of the disease.
Recent studies using gene expression profiling have identified this group as expressing unique cytokeratins that differentiate it from other types of breast cancer and as having a similar poor prognosis to the HER-2 positive group prior to the introduction of trastuzumab (see, e.g., Sorlie T et al., Proc Natl Acad Sci USA. 2001 Sep. 11; 98: 10869-74; Sotiriou C, et al., Proc Natl Acad Sci USA. 2003 September 2; 100(18): 10393-8; and Perou C M, et al., Nature. 2000 Aug. 17; 406(6796):747-52). The profiling data have subgrouped the disease into “luminal”, expressing specific cytokeratins (CK8, CK18) associated with the luminal layer in the normal breast epithelium, or the “basal” group based on the expression of cytokeratins (CK5, CK17) found in the basal layer of the breast epithelium. ER+ and HER2 amplified disease may occur in both subtypes, whereas the “triple negative” breast cancers are generally of the basal subtype (see, e.g., Sorlie T et al., Proc Natl Acad Sci USA. 2001 Sep. 11; 98: 10869-74; Sotiriou C, et al., Proc Natl Acad Sci USA. 2003 Sep. 2; 100(18): 10393-8; Perou C M, et al., Nature. 2000 Aug. 17; 406(6796):747-52; and Wilson Ca et al., Breast Cancer Res. 2004; 6(5):192-200). In addition, there exists a subset of “triple negative” breast cancers that also express vimentin. This group is felt to represent a group of breast cancers that has undergone an epithelial-to-mesenchymal transition (EMT) and has been associated with clinical disease that is more invasive, has a higher mitotic index, and also has a worse clinical outcome (see, e.g., Thomas P A, et al., Clin Cancer Res. 1999 October; 5(10):2698-703 and Laakso M, et al., Clin Cancer Res. 2006 Jul. 15; 12(14 Pt 1):4185-91). Taken together, these data demonstrate that the identification of new therapies with activity in the basal subtype of breast cancer is a clinical priority.